Ischemia-reperfusion (I/R) injury continues to cause significant morbidity and mortality in lung transplantation. Two important pathways which significantly contribute to ischemia-reperfusion injury are the inflammatory response and apoptosis. The transcription factor nuclear factor-kappa B (NF-KappaB) is critical for the maximal expression of many pro-inflammatory mediators. NF-KappaB is also a critical regulator of apoptosis, or programmed cell death. The activation of NF-KappaB is important in the pathogenesis of acute lung injury typical of I/R injury. The overexpression of the anti-inflammatory cytokine Interleukin-10 (IL-10) in experimental lung grafts is effective in significantly ameliorating I/R injury. The aim of this proposal is to study the role of NF-KappaB activation in I/R injury following experimental lung transplantation and the mechanisms by which the overexpression of IL-10 alters these events. An orthotopic rodent left lung transplantation model has proved to be a productive and reliable in vivo model for this investigation. Adenoviral gene transfer of IL-10 by the endobronchial route is an efficient means of establishing IL-10 overexpression in experimental lung grafts. The first aim of this project is to examine the role of NF-KappaB activation in I/R injury. The second aim of this project is to investigate the mechanisms by which gene transfer of IL-10 ameliorates I/R injury.